Non-differential Misclassification Research Articles

Non-differential misclassification of outcome under (near)-perfect specificity: a simulation study.

Mismeasurement of a dichotomous outcome yields an unbiased risk ratio estimate when there are no false positive cases (perfect specificity) and when sensitivity is non-differential with respect to exposure status. In studies where these conditions are expected, quantitative bias analysis may be considered unnecessary. We conducted a simulation study to explore the robustness of this special case to small departures from perfect specificity and stochastic departures from non-differential sensitivity. We observed substantial bias of the risk ratio with specificity values as high at 99.8%. The magnitude of bias increased directly with the true underlying risk ratio and was markedly stronger at lower baseline risk. Stochastic departure from non-differential sensitivity also resulted in substantial bias in most simulated scenarios; downward bias prevailed when sensitivity was higher among unexposed compared with exposed, and upward bias prevailed when sensitivity was higher among exposed compared with unexposed. Our results show that seemingly innocuous departures from perfect specificity (e.g., 0.2%) and from non-differential sensitivity can yield substantial bias of the risk ratio under outcome misclassification. We present a web tool permitting easy exploration of this bias mechanism under user-specifiable study scenarios.

Self-Reported PrEP Use and Risk of Bacterial STIs Among Ontarian Men Who Are Gay or Bisexual or Have Sex With Men.

HIV pre-exposure prophylaxis (PrEP) may increase rates of bacterial sexually transmitted infections (STIs) among gay, bisexual, and other men who have sex with men (GBM) through risk compensation (eg, an increase in condomless sex or number of partners); however, longitudinal studies exploring the time-dependent nature of PrEP uptake and bacterial STIs are limited. We used marginal structural models to estimate the effect of PrEP uptake on STI incidence. We analyzed data from the iCruise study, an online longitudinal study of 535 Ontarian GBM from July 2017 to April 2018, to estimate the effects of PrEP uptake on incidence of self-reported bacterial STIs (chlamydia, gonorrhea, and syphilis) collected with 12 weekly diaries. The incidence rate was calculated as the number of infections per 100 person-months, with evaluation of the STIs overall and individually. We used marginal structural models to account for time-varying confounding and quantitative bias analysis to evaluate the sensitivity of estimates to nondifferential outcome misclassification. Participating GBM were followed up for a total of 1,623.5 person-months. Overall, 70 participants (13.1%) took PrEP during the study period. Relative to no uptake, PrEP uptake was associated with an increased incidence rate of gonorrhea (incidence rate ratio = 4.00; 95% CI, 1.67-9.58), but not of chlamydia or syphilis, and not of any bacterial STI overall. Accounting for misclassification, the median incidence rate ratio for gonorrhea was 2.36 (95% simulation interval, 1.08-5.06). We observed an increased incidence rate of gonorrhea associated with PrEP uptake among Ontarian GBM that was robust to misclassification. Although our findings support current guidelines for integrating gonorrhea screening with PrEP services, additional research should consider the long-term impact of PrEP among this population.Annals Early Access article.

Mobile phone use and brain tumour risk – COSMOS, a prospective cohort study

BackgroundEach new generation of mobile phone technology has triggered discussions about potential carcinogenicity from exposure to radiofrequency electromagnetic fields (RF-EMF). Available evidence has been insufficient to conclude about long-term and heavy mobile phone use, limited by differential recall and selection bias, or crude exposure assessment. The Cohort Study on Mobile Phones and Health (COSMOS) was specifically designed to overcome these shortcomings. MethodsWe recruited participants in Denmark, Finland, the Netherlands, Sweden, and the UK 2007–2012. The baseline questionnaire assessed lifetime history of mobile phone use. Participants were followed through population-based cancer registers to identify glioma, meningioma, and acoustic neuroma cases during follow-up. Non-differential exposure misclassification was reduced by adjusting estimates of mobile phone call-time through regression calibration methods based on self-reported data and objective operator-recorded information at baseline. Hazard ratios (HR) and 95% confidence intervals (CI) for glioma, meningioma, and acoustic neuroma in relation to lifetime history of mobile phone use were estimated with Cox regression models with attained age as the underlying time-scale, adjusted for country, sex, educational level, and marital status. Results264,574 participants accrued 1,836,479 person-years. During a median follow-up of 7.12 years, 149 glioma, 89 meningioma, and 29 incident cases of acoustic neuroma were diagnosed. The adjusted HR per 100 regression-calibrated cumulative hours of mobile phone call-time was 1.00 (95 % CI 0.98–1.02) for glioma, 1.01 (95 % CI 0.96–1.06) for meningioma, and 1.02 (95 % CI 0.99–1.06) for acoustic neuroma. For glioma, the HR for ≥ 1908 regression-calibrated cumulative hours (90th percentile cut-point) was 1.07 (95 % CI 0.62–1.86). Over 15 years of mobile phone use was not associated with an increased tumour risk; for glioma the HR was 0.97 (95 % CI 0.62–1.52). ConclusionsOur findings suggest that the cumulative amount of mobile phone use is not associated with the risk of developing glioma, meningioma, or acoustic neuroma.

Risk of Bias Assessment and Risk Minimisation Strategies in COVID-19 Diagnostic Test Accuracy Study

It is paramount to assess the risk of biases in may arise from diagnostic test accuracy (DTA) study as it will affect the accuracy and validity of the tests. These biases can be found in published researches and here we look at COVID-19 DTA studies. The evaluation of bias risk in diagnostic research is mainly performed using QUADAS-2. The aim of this review was to determine potential selection and information biases in diagnostic test accuracy studies and strategies to minimize risk of biases. Literature review related to diagnostic test accuracy study is identified through an online search of databases namely PubMed, ScienceDirect, Research Gate, Google Scholar, and official government websites range. Six potential biases in four QUADAS-2 domains are identified in COVID-19 diagnostic test accuracy study which are 1) spectrum bias in patient selection; 2) interpretation bias in index test; 3) differential misclassification bias and nondifferential misclassification bias in reference standard; and 4) partial verification bias and differential verification bias in patient flow. The identified biases exert effects on accuracy of COVID-19 diagnostic tests. Six strategies are recommended to reduce these biases, hence, improving the accuracy of COVID-19 diagnostic tests. The best diagnostic test can give benefits to the population in the mass screening program during COVID-19.

Childhood body fatness and the risk of epithelial ovarian cancer: A population-based case-control study in Montreal, Canada

ObjectiveTo assess the association between childhood body fatness and epithelial ovarian cancer (EOC), and whether this association differs by type of EOC. MethodsUsing data from a population-based case-control study (497 cases and 902 controls) in Montreal, Canada conducted 2011–2016, we examined the association between childhood body fatness and EOC, overall and separately for invasive vs. borderline EOCs. A figure rating scale was used to measure body fatness at ages 5 and 10. Multivariable logistic regression was used to estimate adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). Quantitative bias analyses were conducted to assess the impact of exposure misclassification and non-participation. ResultsThe aOR (95% CI) of overall EOC for high vs. low body fatness was 1.07 (0.85–1.34) at age 5 and 1.28 (0.98–1.68) at age 10. The associations were stronger for invasive EOC, specifically the endometrioid histological type. For borderline cancers, the aORs were below the null value with wide confidence intervals. Bias analyses did not reveal a strong influence of non-participation. Non-differential exposure misclassification may have biased aORs towards the null for invasive cancers but did not appear to have an appreciable influence on the aORs for borderline cancers. ConclusionsChildhood body fatness may be a risk factor for invasive EOC in later adult life. Our study highlights the potential importance of examining early life factors for a comprehensive understanding of EOC development.

Does adjustment for non-differential misclassification of dichotomous exposure induce positive bias if there is no true association?

This article is a response to an off-the-record discussion that I had at an international meeting of epidemiologists more than decade ago. It centered on a concern, perhaps widely spread, that adjustment for exposure misclassification can induce a false positive result. I trace the possible history of this supposition and test it in a simulated case-control study under the assumption of non-differential misclassification of binary exposure, in which a Bayesian adjustment is applied. Probabilistic bias analysis is also briefly considered. The main conclusion is that adjustment for the presumed non-differential exposure misclassification of dichotomous does not “induce” positive associations, especially if the focus of the interpretation of the result is taken away from the point estimate. The misconception about positive bias induced by adjustment for exposure misclassification, if more clearly explained during the training of epidemiologists, may promote appropriate (and wider) use of the adjustment techniques. The simple message that can be derived from this paper is: “Exposure misclassification as a tractable problem that deserves much more attention than just a typical qualitative throw-away discussion”.

A prospective cohort study of preconception COVID-19 vaccination and miscarriage.

To what extent is preconception maternal or paternal coronavirus disease 2019 (COVID-19) vaccination associated with miscarriage incidence? COVID-19 vaccination in either partner at any time before conception is not associated with an increased rate of miscarriage. Several observational studies have evaluated the safety of COVID-19 vaccination during pregnancy and found no association with miscarriage, though no study prospectively evaluated the risk of early miscarriage (gestational weeks [GW] <8) in relation to COVID-19 vaccination. Moreover, no study has evaluated the role of preconception vaccination in both male and female partners. An Internet-based, prospective preconception cohort study of couples residing in the USA and Canada. We analyzed data from 1815 female participants who conceived during December 2020-November 2022, including 1570 couples with data on male partner vaccination. Eligible female participants were aged 21-45 years and were trying to conceive without use of fertility treatment at enrollment. Female participants completed questionnaires at baseline, every 8 weeks until pregnancy, and during early and late pregnancy; they could also invite their male partners to complete a baseline questionnaire. We collected data on COVID-19 vaccination (brand and date of doses), history of SARS-CoV-2 infection (yes/no and date of positive test), potential confounders (demographic, reproductive, and lifestyle characteristics), and pregnancy status on all questionnaires. Vaccination status was categorized as never (0 doses before conception), ever (≥1 dose before conception), having a full primary sequence before conception, and completing the full primary sequence ≤3 months before conception. These categories were not mutually exclusive. Participants were followed up from their first positive pregnancy test until miscarriage or a censoring event (induced abortion, ectopic pregnancy, loss to follow-up, 20 weeks' gestation), whichever occurred first. We estimated incidence rate ratios (IRRs) for miscarriage and corresponding 95% CIs using Cox proportional hazards models with GW as the time scale. We used propensity score fine stratification weights to adjust for confounding. Among 1815 eligible female participants, 75% had received at least one dose of a COVID-19 vaccine by the time of conception. Almost one-quarter of pregnancies resulted in miscarriage, and 75% of miscarriages occurred <8 weeks' gestation. The propensity score-weighted IRR comparing female participants who received at least one dose any time before conception versus those who had not been vaccinated was 0.85 (95% CI: 0.63, 1.14). COVID-19 vaccination was not associated with increased risk of either early miscarriage (GW: <8) or late miscarriage (GW: 8-19). There was no indication of an increased risk of miscarriage associated with male partner vaccination (IRR = 0.90; 95% CI: 0.56, 1.44). The present study relied on self-reported vaccination status and infection history. Thus, there may be some non-differential misclassification of exposure status. While misclassification of miscarriage is also possible, the preconception cohort design and high prevalence of home pregnancy testing in this cohort reduced the potential for under-ascertainment of miscarriage. As in all observational studies, residual or unmeasured confounding is possible. This is the first study to evaluate prospectively the relation between preconception COVID-19 vaccination in both partners and miscarriage, with more complete ascertainment of early miscarriages than earlier studies of vaccination. The findings are informative for individuals planning a pregnancy and their healthcare providers. This work was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute of Health [R01-HD086742 (PI: L.A.W.); R01-HD105863S1 (PI: L.A.W. and M.L.E.)], the National Institute of Allergy and Infectious Diseases (R03-AI154544; PI: A.K.R.), and the National Science Foundation (NSF-1914792; PI: L.A.W.). The funders had no role in the study design, data collection, analysis and interpretation of data, writing of the report, or the decision to submit the paper for publication. L.A.W. is a fibroid consultant for AbbVie, Inc. She also receives in-kind donations from Swiss Precision Diagnostics (Clearblue home pregnancy tests) and Kindara.com (fertility apps). M.L.E. received consulting fees from Ro, Hannah, Dadi, VSeat, and Underdog, holds stock in Ro, Hannah, Dadi, and Underdog, is a past president of SSMR, and is a board member of SMRU. K.F.H. reports being an investigator on grants to her institution from UCB and Takeda, unrelated to this study. S.H.-D. reports being an investigator on grants to her institution from Takeda, unrelated to this study, and a methods consultant for UCB and Roche for unrelated drugs. The authors report no other relationships or activities that could appear to have influenced the submitted work. N/A.

Exposure to pesticides and risk of Hodgkin lymphoma in an international consortium of agricultural cohorts (AGRICOH)

PurposeSome pesticides may increase the risk of certain lymphoid malignancies, but few studies have examined Hodgkin lymphoma (HL). In this exploratory study, we examined associations between agricultural use of 22 individual active ingredients and 13 chemical groups and HL incidence.MethodsWe used data from three agricultural cohorts participating in the AGRICOH consortium: the French Agriculture and Cancer Cohort (2005–2009), Cancer in the Norwegian Agricultural Population (1993–2011), and the US Agricultural Health Study (1993–2011). Lifetime pesticide use was estimated from crop-exposure matrices or self-report. Cohort-specific covariate-adjusted overall and age-specific (< 40 or ≥ 40 years) hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression and combined using random effects meta-analysis.ResultsAmong 316 270 farmers (75% male) accumulating 3 574 815 person-years at risk, 91 incident cases of HL occurred. We did not observe statistically significant associations for any of the active ingredients or chemical groups studied. The highest risks of HL overall were observed for the pyrethroids deltamethrin (meta-HR = 1.86, 95% CI 0.76–4.52) and esfenvalerate (1.86, 0.78–4.43), and inverse associations of similar magnitude were observed for parathion and glyphosate. Risk of HL at ≥ 40 years of age was highest for ever-use of dicamba (2.04, 0.93–4.50) and lowest for glyphosate (0.46, 0.20–1.07).ConclusionWe report the largest prospective investigation of these associations. Nonetheless, low statistical power, a mixture of histological subtypes and a lack of information on tumour EBV status complicate the interpretability of the results. Most HL cases occurred at older ages, thus we could not explore associations with adolescent or young adult HL. Furthermore, estimates may be attenuated due to non-differential exposure misclassification. Future work should aim to extend follow-up and refine both exposure and outcome classification.

P-447 Gestational weight gain in relation to time-to-pregnancy and conception by assisted reproductive technology

Abstract Study question Does the gestational weight gain trajectory differ across levels of time-to-pregnancy (TTP) for spontaneously conceived pregnancies and pregnancies conceived by assisted reproductive technology (ART)? Summary answer Women with ART pregnancies had lower weekly weight gain during the third trimester compared with women with spontaneous conceptions with TTP ≤3. What is known already Studies suggest that both prolonged TTP and conception by ART may increase the risk of pregnancy complications and affect perinatal outcomes such as birthweight. Suboptimal gestational weight gain might further increase the risk of adverse pregnancy outcomes. However, it remains unclear whether there may be differences in gestational weight gain according to TTP and ART, which contribute to the subsequent risk of adverse pregnancy outcomes. Study design, size, duration We studied 69,121 singleton planned pregnancies contributed by 60,847 women participating in the Norwegian Mother, Father and Child Cohort Study. Participants completed questionnaires at 15 weeks’ gestation (study entry), 30 weeks’ gestation, and six months postpartum on sociodemographic, reproductive, and behavioral factors. Participants reported their TTP, and up to four weight measurements and corresponding gestational age from preconception through delivery. We identified use of ART in the Medical Birth Registry of Norway. Participants/materials, setting, methods We fitted gestational weight gain trajectories using mixed-effects linear regression models and included an interaction term between time (gestational weeks) and the exposure groups, TTP ≤3 (reference); TTP 4-6; TTP 7-11, TTP ≥12 months, and ART, to assess differences across levels of TTP and conception by ART. The analyses were adjusted for maternal age at start of pregnancy, pre-pregnancy height, educational attainment, pre-pregnancy smoking, parity, and gestational age at birth. Main results and the role of chance The adjusted average weekly weight gain was -15g (95% CI: −19; −12) during the first trimester, 620g (95% CI: 615; 624) during the second trimester, and 491g (95% CI: 489; 494) during the third trimester. When we compared differences in average weekly weight change during the first trimester, we observed little difference between the exposure groups. During the second trimester, compared with TTP≤3 months women with TTP 4-6 months, TTP 7-11 months or TTP ≥12 months gained on average 7g (95% CI: −18; 3), 19g (95% CI: −33; −5) and 15g (95% CI: −29; −1) less per week, respectively, whereas women with ART pregnancies gained 11g more per week (95% CI: −13; 34). However, the results for TTP 4-6 and ART pregnancies were imprecise. During the third trimester, average weekly weight gain did not differ according to TTP for spontaneous conceptions, while women who conceived after ART gained 35g (95% CI: −49; −22) less than women with TTP≤3 each week. Limitations, reasons for caution Because TTP and gestational weight gain were self-reported, non-differential misclassification may have influenced our results. Wider implications of the findings Decelerated weight gain during the third trimester in ART pregnancies compared with women who conceived spontaneously within 3 months might be associated with adverse pregnancy outcomes. Although our findings are imprecise and need to be replicated, monitoring gestational weight gain trajectories might support identification of pregnancies at increased risk. Trial registration number Not applicable

P-781 Assisted reproductive technology-associated risk factors for retained placenta

Abstract Study question What are the assisted reproductive technology-associated risk factors for retained products of conception (RPOC) following delivery? Summary answer Frozen embryo transfer (FET) with hormone replacement cycles (HRC) constitutes the largest risk factor for RPOC. What is known already RPOC is a key cause of secondary postpartum hemorrhage. Previous studies have shown that the use of ART increases the risk of RPOC and subsequent transfusion following delivery. However, the relationships between specific ART-treatment factors and the risk of RPOC have not been elucidated. Study design, size, duration We performed a registry-based retrospective cohort study using the Japanese national ART registry, in which all the ART cycles performed in Japan are recorded including the perinatal outcomes. Participants/materials, setting, methods Singleton live births between 2007 and 2017 were studied (n = 306,411). Odds ratios (ORs) and 95% confidence intervals (CIs) for the potential risk factors for RPOC associated with fresh and frozen cycles were obtained from multiple logistic regression analysis, incorporating adjustment for maternal age, infertility, and calendar year. Because information regarding assisted hatching (AH) and HRC for endometrial preparation only became available in 2012, these factors were analysed using the data collected between 2012 and 2017. Main results and the role of chance RPOC was diagnosed for 132 deliveries (0.04%), of which 122 (92.4%) followed FET cycles and only 10 (0.01%) followed fresh embryo transfer (ET). No significant risk factors for RPOC were identified using the fresh ET data. For FET cycles, the use of HRC as an endometrial preparation method represented the largest risk factor (adjusted OR, 4.9; 95% CI, 2.0 to 12.3), with RPOC occurring in 0.05% of deliveries following HRC (51/97, 958 deliveries) but in only 0.01% following natural cycles (5/47, 79 deliveries). AH was also associated with a significantly higher risk of RPOC (adjusted OR, 1.9; 95% CI, 1.2 to 3.1), although the risk was lower than that associated with HRC). Subgroup analysis showed that these significant associations of HRC and AH with RPOC were present for transvaginal deliveries, but not deliveries by caesarean section. Limitations, reasons for caution The registry lacks important information regarding risk factors for RPOC, such as parity, body mass index, and history of previous uterine surgery. Furthermore, the lower prevalence of RPOC in the present study (0.04%) than in other studies (approximately 1%) suggests the possibility of non-differential misclassification for the outcomes of RPOC. Wider implications of the findings Although the possibility of residual confounding factors remains, the present findings suggest that additional care should be taken in the management of patients undergoing vaginal deliveries following FET who have HRC or AH. Trial registration number Not applicable

Association of male fatty acid intake with fecundability among couples planning pregnancy.

To what extent is male fatty acid intake associated with fecundability among couples planning pregnancy? We observed weak positive associations of male dietary intakes of total and saturated fatty acids with fecundability; no other fatty acid subtypes were appreciably associated with fecundability. Male fatty acid intake has been associated with semen quality in previous studies. However, little is known about the extent to which male fatty acid intake is associated with fecundability among couples attempting spontaneous conception. We conducted an internet-based preconception prospective cohort study of 697 couples who enrolled during 2015-2022. During 12 cycles of observation, 53 couples (7.6%) were lost to follow-up. Participants were residents of the USA or Canada, aged 21-45 years, and not using fertility treatment at enrollment. At baseline, male participants completed a food frequency questionnaire from which we estimated intakes of total fat and fatty acid subtypes. We ascertained time to pregnancy using questionnaires completed every 8 weeks by female participants until conception or up to 12 months. We used proportional probabilities regression models to estimate fecundability ratios (FRs) and 95% CIs for the associations of fat intakes with fecundability, adjusting for male and female partner characteristics. We used the multivariate nutrient density method to account for energy intake, allowing for interpretation of results as fat intake replacing carbohydrate intake. We conducted several sensitivity analyses to assess the potential for confounding, selection bias, and reverse causation. Among 697 couples, we observed 465 pregnancies during 2970 menstrual cycles of follow-up. The cumulative incidence of pregnancy during 12 cycles of follow-up after accounting for censoring was 76%. Intakes of total and saturated fatty acids were weakly, positively associated with fecundability. Fully adjusted FRs for quartiles of total fat intake were 1.32 (95% CI 1.01-1.71), 1.16 (95% CI 0.88-1.51), and 1.43 (95% CI 1.09-1.88) for the second, third, and fourth vs the first quartile, respectively. Fully adjusted FRs for saturated fatty acid intake were 1.21 (95% CI 0.94-1.55), 1.16 (95% CI 0.89-1.51), and 1.23 (95% CI 0.94-1.62) for the second, third, and fourth vs the first quartile, respectively. Intakes of monounsaturated, polyunsaturated, trans-, omega-3, and omega-6 fatty acids were not strongly associated with fecundability. Results were similar after adjustment for the female partner's intakes of trans- and omega-3 fats. Dietary intakes estimated from the food frequency questionnaire may be subject to non-differential misclassification, which is expected to bias results toward the null in the extreme categories when exposures are modeled as quartiles. There may be residual confounding by unmeasured dietary, lifestyle, or environmental factors. Sample size was limited, especially in subgroup analyses. Our results do not support a strong causal effect of male fatty acid intakes on fecundability among couples attempting to conceive spontaneously. The weak positive associations we observed between male dietary fat intakes and fecundability may reflect a combination of causal associations, measurement error, chance, and residual confounding. The study was funded by the National Institutes of Health, grant numbers R01HD086742 and R01HD105863. In the last 3 years, PRESTO has received in-kind donations from Swiss Precision Diagnostics (home pregnancy tests) and Kindara.com (fertility app). L.A.W. is a consultant for AbbVie, Inc. M.L.E. is an advisor to Sandstone, Ro, Underdog, Dadi, Hannah, Doveras, and VSeat. The other authors have no competing interests to report. N/A.

The directionality of measurement bias: a directed acyclic graph-based structural perspective

Measurement bias (MB) has been described in causal structures but is still not entirely clear. In practice, the correctness of substitution estimate (SE) of effect is a prerequisite for causal inference, usually based on a bidirectionally non-differential misclassification between the measured exposure and the measured outcome. Based on a directed acyclic graph (DAG), this paper proposes a structure for the single-variable measure, where its MB is derived from the choice of an imperfect, "input/output device-like" measurement system. The MB of the SE is influenced both by the measurement system itself and by factors outside the measurement system: while the independence or dependence mechanism of the measurement system still ensures that the MB of the SE is bidirectionally non-differential; however, the misclassification can be bidirectionally non-differential, unidirectionally differential, or bidirectionally differential resulted from the factors outside the measurement system. In addition, reverse causality should be defined at the level of measurement, where measured exposures can influence measured outcomes and vice versa. Combined with temporal relationships, DAGs help elucidate MB's structures, mechanisms, and directionality.

The matrix revolutions: How databases and database linkages will transform epidemiologic research.

The matrix revolutions: How databases and database linkages will transform epidemiologic research.

Evidence-Based Medicine in Otolaryngology Part 14: Falsehood and Bias.

Falsehood and bias can have tangible effects, whether related to the "hoax" of Corona virus disease/COVID-19 or the impact of personal protective equipment in city-wide news. The spread of false information requires the diversion of time and resources into rebolstering the truth. Our objective is thus to elucidate types of bias that may influence our daily work, along with ways to mitigate them. Publications are included which delineate specific aspects of bias or address how to preempt, mitigate, or correct bias, whether conscious or unconscious. We discuss: (1) the background and rationale for proactively considering potential sources of bias, (2) relevant definitions and concepts, (3) potential means to limit effects of inaccurate data sources, and (4) evolving frontiers in the management of bias. In doing so, we review epidemiological concepts and susceptibility to bias within study designs, including database studies, observational studies, randomized controlled trials (RCTs), systematic reviews, and meta-analyses. We additionally discuss concepts such as the difference between disinformation and misinformation, differential or nondifferential misclassification, bias toward a null result, and unconscious bias, among others. We have the means to mitigate sources of potential bias in database studies, observational studies, RCTs, and systematic reviews, beginning with education and awareness. False information may spread faster than true information, so it is beneficial to understand potential sources of falsehood we face, in order to safeguard our daily impressions and decisions. Awareness of potential sources of falsehood and bias forms the foundation for accuracy in our everyday work.

Self-reported Human Papillomavirus Vaccination and Vaccine Effectiveness Among Men Who Have Sex with Men: A Quantitative Bias Analysis.

Self-report of human papillomavirus (HPV) vaccination has ~80-90% sensitivity and ~75-85% specificity. We measured the effect of nondifferential exposure misclassification associated with self-reported vaccination on vaccine effectiveness (VE) estimates. Between 2017-2019, we recruited sexually active gay, bisexual, and other men who have sex with men aged 16-30 years in Canada. VE was derived as 1-prevalence ratio × 100% for prevalent anal HPV infection comparing vaccinated (≥1 dose) to unvaccinated men using a multivariable modified Poisson regression. We conducted a multidimensional and probabilistic quantitative bias analysis to correct VE estimates. Bias-corrected VE estimates were relatively stable across sensitivity values but differed from the uncorrected estimate at lower values of specificity. The median adjusted VE was 27% (2.5-97.5th simulation interval = -5-49%) in the uncorrected analysis, increasing to 39% (2.5-97.5th simulation interval = 2-65%) in the bias-corrected analysis. A large proportion of participants erroneously reporting HPV vaccination would be required to meaningfully change VE estimates.

Pathogen exposure misclassification can bias association signals in GWAS of infectious diseases when using population-based common control subjects

Genome-wide association studies (GWASs) have been performed to identify host genetic factors for a range of phenotypes, including for infectious diseases. The use of population-based common control subjects from biobanks and extensive consortia is a valuable resource to increase sample sizes in the identification of associated loci with minimal additional expense. Non-differential misclassification of the outcome has been reported when the control subjects are not well characterized, which often attenuates the true effect size. However, for infectious diseases the comparison of affected subjects to population-based common control subjects regardless of pathogen exposure can also result in selection bias. Through simulated comparisons of pathogen-exposed cases and population-based common control subjects, we demonstrate that not accounting for pathogen exposure can result in biased effect estimates and spurious genome-wide significant signals. Further, the observed association can be distorted depending upon strength of the association between a locus and pathogen exposure and the prevalence of pathogen exposure. We also used a real data example from the hepatitis C virus (HCV) genetic consortium comparing HCV spontaneous clearance to persistent infection with both well-characterized control subjects and population-based common control subjects from the UK Biobank. We find biased effect estimates for known HCV clearance-associated loci and potentially spurious HCV clearance associations. These findings suggest that the choice of control subjects is especially important for infectious diseases or outcomes that are conditional upon environmental exposures.

When Does Differential Outcome Misclassification Matter for Estimating Prevalence?

When accounting for misclassification, investigators make assumptions about whether misclassification is "differential" or "nondifferential." Most guidance on differential misclassification considers settings where outcome misclassification varies across levels of exposure, or vice versa. Here, we examine when covariate-differential misclassification must be considered when estimating overall outcome prevalence. We generated datasets with outcome misclassification under five data generating mechanisms. In each, we estimated prevalence using estimators that (a) ignored misclassification, (b) assumed misclassification was nondifferential, and (c) allowed misclassification to vary across levels of a covariate. We compared bias and precision in estimated prevalence in the study sample and an external target population using different sources of validation data to account for misclassification. We illustrated use of each approach to estimate HIV prevalence using self-reported HIV status among people in East Africa cross-border areas. The estimator that allowed misclassification to vary across levels of the covariate produced results with little bias for both populations in all scenarios but had higher variability when the validation study contained sparse strata. Estimators that assumed nondifferential misclassification produced results with little bias when the covariate distribution in the validation data matched the covariate distribution in the target population; otherwise estimates assuming nondifferential misclassification were biased. If validation data are a simple random sample from the target population, assuming nondifferential outcome misclassification will yield prevalence estimates with little bias regardless of whether misclassification varies across covariates. Otherwise, obtaining valid prevalence estimates requires incorporating covariates into the estimators used to account for misclassification.

Work-related stress and atopic dermatitis: Results from the study on occupational allergy risks

Chronic stress at work is ubiquitous in modern societies. However, its influence on atopic dermatitis (AD) has hardly been investigated. This study aimed to elucidate the association between work-related stress and AD via a longitudinal study. The analysis comprised data from three phases (2002–2003, 2007–2009, 2017–2018) of the prospective Study on Occupational Allergy Risks (SOLAR), including 1,240 young adults aged 16 to 18 years at baseline (61% female) who were originally recruited for the International Study of Asthma and Allergies in Childhood Phase II in 1995–1996. AD was assessed at all three phases based on self-reports of a physician’s diagnosis and symptoms. Work-related stress was measured at all three periods using the work discontent and work overload scales from the Trier Inventory for the Assessment of Chronic Stress with adaptions to school and university. Generalized estimating equations were used to analyze the association between stress and AD, treating work discontent and work overload first as continuous and then as categorical exposure variables. We observed 50 AD cases (4%) at SOLAR I, 48 (4%) at SOLAR II, and 42 (3%) at SOLAR III. A one-point increase in the work discontent score was associated with an odds ratio (OR) for AD of 1.05 (95% confidence interval [CI], 1.00–1.10). The respective increase in the work overload score led to an OR of 1.03 (95% CI, 0.99–1.06). In the categorical analysis, there was no clear indication of elevated odds of AD in the highest vs. lowest exposure group (4th vs. 1st quartile: OR, 1.53; 95% CI, 0.92–2.53 for work discontent; OR, 1.38, 95% CI, 0.83–2.27 for work overload). Altogether, we observed limited to no evidence for an association between work-related stress and AD. Our study’s ability to detect stronger evidence may have been compromised by shortcomings such as nondifferential misclassification of the outcome or insufficient statistical precision due to small numbers of AD cases. Another explanation could be that AD predominantly becomes evident in childhood, not in adulthood.

Associations between maternal urinary isoflavone concentrations and anogenital distance of offspring throughout infancy: a prospective cohort study.

Are maternal urinary isoflavone (ISO) concentrations during pregnancy associated with anogenital distance (AGD) in infants at birth, and at 6 and 12 months of age? Higher maternal urinary ISO concentrations during pregnancy were associated with longer AGD in infants of both sexes, and equol (EQU) and daidzein (DAD) were identified as the important ISO mixture components in the observed associations. Evidence of the association of prenatal exposure to ISO with offspring's AGD is mainly derived from animal studies, which used different study designs and had inconsistent results. Only one human study has been reported and it found null associations between maternal ISO exposure during pregnancy and AGD among boys at birth, with a small sample size and a wide range of exposure windows. No human study on girls was found. Prospective cohort study (Shanghai-Minhang Birth Cohort Study), with pregnant women recruited at 12-16 weeks of gestation in Shanghai, China between April and December 2012. One thousand two hundred and twenty-five live singletons were left in the cohort at delivery of which 480 mother-infant pairs had data on both maternal urinary ISO concentrations and at least one AGD measurement and were included in the present study. Anopenile distance (AGDAP) and anoscrotal distance (AGDAS) of boys and anoclitoral distance (AGDAC) and anofourchette distance (AGDAF) of girls were measured at birth and at 6 and 12 months of age. Multiple linear regression models were used to examine the associations between maternal ISO concentrations and AGD. Bayesian kernel machine regression (BKMR) was implemented to examine both the overall effects of ISO mixture and the single effect of each ISO and identify important components of ISO mixture. A general profile of higher concentrations of maternal ISO associated with longer AGD in infants of both sexes was observed, when maternal education, parity, BMI before pregnancy (BMI, categorical variable), passive smoking during early pregnancy, age at delivery, gestational weeks and infant body size were adjusted for. Among boys, EQU was associated with increased AGDAS at birth and at 6 and 12 months, and DAD was associated with increased AGDAP at birth. Among girls, the associations of EQU and DAD with increased AGDAC and AGDAF at birth were found. When gestational weight gain and feeding patterns of infants in the first 6 months were additionally adjusted for, and maternal BMI was adjusted for as a continuous variable, more pronounced associations were observed, especially for associations of genistein (GEN), DAD and glycitein (GLY) with increased AGDAP and AGDAS at 6 months in boys. However, these associations were not always observed in the highest tertile group, and no consistent dose-response relationships were found. Similar results were observed in BKMR models, showing positive correlations of concentration of ISO mixture with increased AGDAS at both 6 and 12 months among boys, and increased AGDAC and AGDAF at birth among girls. Statistically significant increments of 4.96 mm (95% credible interval (CrI): 1.40, 8.52) and 1.07 mm (95% CrI: 0.02, 2.13) in AGDAS at 6 months among boys and AGDAC at birth among girls, respectively, were observed at the 75th percentile of ISO mixture, compared with 25th percentile. EQU and DAD were identified as the important components among ISO-AGD associations. First, due to the short half-lives of ISO, the accuracy of a single spot urine sample reflecting ISO exposure during pregnancy may be limited, and thus may cause non-differential misclassification. Second, despite the adjustments for several important covariates in the study, unmeasured and residual confounding factors may remain a concern. Third, false discovery due to multiple testing may remain. Finally, the reduced sample sizes attributed to the loss of follow-up and missing data of confounders may limit our ability to detect an association, if any existed. Prenatal ISO exposure may affect the reproductive development of offspring. As ISO can be widely detected in pregnant women, especially in Eastern countries, more studies are warranted to provide evidence of the effects of prenatal ISO exposure on long-term reproductive outcomes. This work was supported by grants from the National Key Research and Development Program of China (2021YFC2701003), the National Natural Science Foundation of China (22076123), the Science and Technology Commission of Shanghai Municipality (21ZR1454700 and 20ZR1448000), the Shanghai Municipal Health Commission (20194Y0160) and Innovation-oriented Science and Technology Grant from NHC Key Laboratory of Reproduction Regulation (CX2022-04). The authors have no conflicts of interest to declare. N/A.

Study of Parental Occupational Exposures to Solvents and Risk of Autism Spectrum Disorder in Offspring

BACKGROUND AND AIM: Solvents can accumulate in fat and later metabolize during pregnancy. Additionally, these toxicants could lead to germline mutations. We investigated associations between multiple parental occupational solvent exposures and odds of autism spectrum disorder (ASD) diagnosis in offspring. METHODS: Using population-based data from the Danish National Patient Registry, we identified a subset of ASD cases from 1982 to 2016 and 1:100 sex and birth-year matched controls obtained from the Central Population Register. We determined parental occupation history from age 16 years through 6 months post-childbirth from the Danish Pension Fund and estimated cumulative benzene, methylcyclohexane, toluene, trichloroethylene, perchloroethylene, and 1,1,1-trichloroethane exposure for mothers and fathers based on job exposure matrices (JEMs). Conditional logistic regression was used to estimate adjusted odds ratios (aOR) and 95% confidence intervals (CI) for exposures one year prior to conception and during pregnancy. RESULTS: In analysis of data from 1898 people with ASD and 141,702 without ASD, there were no observed associations between maternal solvent exposures during pregnancy and risk of ASD in offspring. However, analysis for maternal benzene exposure one year prior to conception revealed higher adjusted odds for those with any exposure (aOR=1.55; 95% CI 1.02, 2.37). Additionally, although there were no significant associations between paternal solvent exposures during pregnancy and ASD risk, there were significantly increased odds of ASD in offspring whose fathers were exposed to benzene (aOR=3.07; 95% CI 1.72, 5.46) and toluene (aOR=1.66; 95% CI 1.05, 2.62) one year before conception. CONCLUSIONS: Although previous studies have suggested parental solvent exposure during pregnancy can contribute to pathogenesis of ASD, our findings suggest that risk may be increased through exposures prior to conception. However, unavoidable non-differential misclassification from the use of JEMs may have masked truly increased risk during pregnancy.